Substituted pyrazole kinase inhibitors

ABSTRACT

The present invention is directed to novel substituted pyrazole compounds of Formula (I) or a form or composition thereof 
     
       
         
         
             
             
         
       
     
     and the use thereof as inhibitors of ATP-protein kinase interactions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority of the filing date of U.S. Provisionalapplication Ser. No. 60/829,729 filed Oct. 17, 2006, entitled“Substituted Pyrazole Kinase Inhibitors,” the entire disclosure of whichare hereby incorporated by reference into the present disclosure.

FIELD OF THE INVENTION

The present invention is in the area of novel benzimidazole substitutedpyrazole compounds or forms thereof, their synthesis and their use askinase inhibitors.

BACKGROUND OF THE INVENTION

In general, protein kinases are the largest set of structurally relatedphosphoryl transferases, have highly conserved structures and catalyticfunctions and may be categorized into families by the substrates theyphosphorylate (e.g., protein-tyrosine, protein-serine/threonine,histidine and the like) and are responsible for the control of a widevariety of cellular signal transduction processes.

Protein kinases catalyze and regulate the process of phosphorylation.Phosphorylation modulates or regulates a variety of cellular processessuch as proliferation, growth, differentiation, metabolism, apoptosis,motility, transcription, translation, and other signaling processes.Uncontrolled signaling for cell growth due to defective control ofprotein phosphorylation has also been implicated in a number ofdiseases.

Phosphorylation modulates or regulates a variety of cellular processessuch as proliferation, growth, differentiation, metabolism, apoptosis,motility, transcription, translation and other signaling processes.Defective control of protein phosphorylation due to unregulated cellularmitosis, unregulated cell proliferation and upregulated kinase activityhas been implicated in a number of diseases and disease conditions, suchas osteoarthritis, rheumatoid arthritis, synovial pannus invasion inarthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus,diabetic angiopathy, diabetic retinopathy, retinal vessel proliferation,inflammatory bowel disease, Crohn's disease, ulcerative colitis, bonediseases, transplant or bone marrow transplant rejection, lupus, chronicpancreatitis, cachexia, septic shock, fibroproliferative anddifferentiative skin diseases or disorders, central nervous systemdiseases, neurodegenerative diseases, disorders or conditions related tonerve damage and axon degeneration subsequent to a brain or spinal cordinjury, acute or chronic cancer, ocular diseases, viral infections,heart disease, lung or pulmonary diseases or kidney or renal diseases.Therefore, kinase inhibitors have potential use as therapeutic agents.

There is a need for potent small-molecule kinase inhibitors of one ormore of the CDK1, HER2, VEGFR2, or Aurora-A kinase proteins and the likepossessing anti-tumor cell proliferation activity, and as such areuseful for treating a CDK1, HER2, VEGFR2, or Aurora-A kinase receptormediated, angiogenesis-mediated or hyperproliferative disorders.

United States Patent Application 2006/0014756 describes benzimidazolesas kinase inhibitors.

SUMMARY OF THE INVENTION

A first aspect of the present invention is novel compounds of Formula(I) or a form thereof:

as inhibitors of ATP-protein kinase interactions, wherein R₁, R₂, R₃ andR₄ are as defined herein.

A sec aspect of this invention is a composition or medicament comprisingone or more compounds of Formula (I) or a form thereof.

A third aspect of this invention is a method of synthesizing compoundsof Formula (I) or a form thereof.

A fourth aspect of this invention is the use of one or more compounds ofFormula (I) or a form thereof as protein kinase inhibitors. The aspectof the protein kinases includes serine/threonine kinases and tyrosinekinases. The aspect of the kinases further includes kinase selected fromCDK1, HER2, VEGFR2, or Aurora-A. Also in this aspect, the compounds ofFormula (I) or a form thereof are useful for preventing, treating orameliorating chronic or acute kinase mediated diseases.

A fifth aspect of this invention is a method for ameliorating, treatingor preventing a chronic or acute kinase mediated disease in a patient inneed thereof comprising administering to the patient an effective amountof one or more compounds of Formula (I) or a form thereof.

In this aspect, the chronic or acute disease is mediated by a kinaseselected from CDK1, HER2, VEGFR2, or Aurora-A. Also in this aspect, themethod includes inhibiting unregulated kinase activity in the patient.The aspect of unregulated kinase activity includes unregulated kinaseexpression or signaling, unregulated expression or signaling of a kinaseselected from CDK1, HER2, VEGFR2, or Aurora-A and unregulated expressionor signaling which results in unregulated cell proliferation. The aspectof unregulated cell proliferation includes cancer, metastatic cancercell invasion or metastatic cancer cell migration. The aspect of cancerincludes tumors mediated by the unregulated activity of kinases selectedfrom CDK1, HER2, VEGFR2, or Aurora-A. The aspect of cancer furtherincludes non-small-cell lung cancers, colon cancers, breast cancers andthe like. An aspect of the method includes an amount of one or morecompounds of Formula (I) or a form thereof which is effective to induceremission of a chronic form of a cancer. The aspect of the effectiveamount includes an amount, which is effective at a low dose to inhibitunregulated kinase activity.

A sixth aspect of this invention is a method for use of one or morecompounds of Formula (I) or a form thereof in the preparation of acomposition or medicament for preventing, treating or amelioratingchronic or acute kinase mediated diseases in a patient in need thereof.This aspect of the method includes administering to the patient aneffective amount of a compound of Formula (I) or a form thereof in theform of a composition or medicament.

These and other aspects and advantages of the invention, which willbecome apparent in light of the detailed description below, are achievedthrough use of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pyrazole compounds of Formula (I):

and a form thereof, wherein

-   R₁ is hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, amino or    C₁₋₆alkyl-amino;-   R₂ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,    C₁₋₆alkyl-amino, amino-C₁₋₆alkyl, C₁₋₆alkyl-amino-C₁₋₆alkyl,    C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano;-   R₃ is hydrogen or C₁₋₆alkyl; alternatively, R₂ and R₃ are taken    together to form —CH═CH—CH═CH—; and,-   R₄ is hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy or heterocyclyl, wherein said    heterocyclyl is optionally substituted with C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein

-   R₁ is hydrogen, halo or amino;-   R₂ is hydrogen, C₁₋₆alkoxy, C₁₋₆alkyl-amino-C₁₋₆alkyl,    C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano;-   R₃ is hydrogen or C₁₋₆alkyl; alternatively, R₂ and R₃ are taken    together to form —CH═CH—CH═CH—; and,-   R₄ is hydrogen, C₁₋₆alkoxy or heterocyclyl, wherein heterocyclyl is    optionally substituted with C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein

-   R₁ is hydrogen, chloro or amino;-   R₂ is hydrogen, C₁₋₆alkoxy, C₁₋₆alkyl-amino-C₁₋₆alkyl,    C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano;-   R₃ is hydrogen or C₁₋₆alkyl;-   alternatively, R₂ and R₃ are taken together to form —CH═CH—CH═CH—;    and,-   R₄ is hydrogen, C₁₋₆alkoxy or piperazine, wherein piperazine is    substituted with C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein

-   R₁ is hydrogen, chloro or amino;-   R₂ is hydrogen, methoxy, ethyl-amino-methyl, methoxy-carbonyl,    ethyl-amino-carbonyl or cyano;-   R₃ is hydrogen or methyl;-   alternatively, R₂ and R₃ are taken together to form —CH═CH—CH═CH—;    and,-   R₄ is hydrogen, methoxy or piperazine, wherein piperazine is    substituted with methyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₁ is hydrogen, halo or amino.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₁ is hydrogen, chloro or amino.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₂ is hydrogen, C₁₋₆alkoxy,C₁₋₆alkyl-amino-C₁₋₆alkyl, C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonylor cyano.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₂ is hydrogen, methoxy, ethyl-amino-methyl,methoxy-carbonyl, ethyl-amino-carbonyl or cyano.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₃ is hydrogen.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₃ is C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₃ is hydrogen or methyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₃ is methyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₄ is hydrogen, C₁₋₆alkoxy or heterocyclyl, whereinheterocyclyl is optionally substituted with C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₄ is hydrogen, C₁₋₆alkoxy or piperazine, whereinpiperazine is substituted with C₁₋₆alkyl.

An example of the present invention is a compound of Formula (I) and aform thereof wherein R₄ is hydrogen, methoxy or piperazine, whereinpiperazine is substituted with methyl.

Compounds representative of a compound of Formula (I) or a form thereofinclude compounds and forms thereof selected from:

Compound Forms

The term “form” means, in reference to compounds of the presentinvention, such may exist as, without limitation, a salt, stereoisomer,tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester,prodrug or metabolite form. The present invention encompasses all suchcompound forms and mixtures thereof.

The term “isolated form” means, in reference to compounds of the presentinvention, such may exist in an essentially pure state such as, withoutlimitation, an enantiomer, a racemic mixture, a geometric isomer (suchas a cis or trans stereoisomer), a mixture of geometric isomers, and thelike. The present invention encompasses all such compound forms andmixtures thereof.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which may, for example,be formed by mixing a solution of the compound according to theinvention with a solution of an acid such as acetic acid, adipic acid,benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid,hydrochloric acid, maleic acid, malonic acid, phosphoric acid,saccharinic acid, succinic acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable salts thereof may include alkali metal salts, e.g.sodium or potassium salts; alkaline earth metal salts, e.g. calcium ormagnesium salts; and salts formed with suitable organic ligands, e.g.quaternary ammonium salts.

Thus, representative salts include the following: acetate, adipate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate,glutamate, glyconate, hydrabamine, hydrobromine, hydrochloride, iodide,isothionate, lactate, malate, maleate, malonate, mandelate, mesylate,nitrate, oleate, pamoate, palmitate, phosphate/diphosphate,saccharinate, salicylate, stearate, sulfate, succinate, tartrate,tosylate, trichloroacetate, trifluoroacetate and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999.The protecting groups may be removed at a convenient subsequent stageusing methods known in the art. The scope of the present inventionencompasses all such protected compound forms and mixtures thereof.

The invention includes compounds of various isomers and mixturesthereof. The term “isomer” refers to compounds that have the samecomposition and molecular weight but differ in physical and/or chemicalproperties. Such substances have the same number and kind of atoms butdiffer in structure. The structural difference may be in constitution(geometric isomers) or in an ability to rotate the plane of polarizedlight (optical isomers).

The term “stereoisomer” refers to a isomers that have the same molecularformula and the same sequence of covalently bonded atoms but a differentspatial orientation.

The term “optical isomer” means isomers of identical constitution thatdiffer only in the spatial arrangement of their groups. Optical isomersrotate the plane of polarized light in different directions. The term“optical activity” means the degree to which an optical isomer rotatesthe plane of polarized light.

The term “racemate” or “racemic mixture” means an equimolar mixture oftwo enantiomeric species, wherein each of the isolated species rotatesthe plane of polarized light in the opposite direction such that themixture is devoid of optical activity.

The term “enantiomer” means a stereoisomer that is not nonsuperimposablewith its mirror image. The term “diastereomer” means stereoisomers thatare not enantiomers.

The term “chiral molecule” means a molecule that has at least one pairof enantiomers. This is in contrast to achiral molecules, which can besuperimposed on their mirror images.

The two distinct mirror image versions of the chiral molecule are alsoknown as levo (left-handed), abbreviated L, or dextro (right-handed),abbreviated D, depending on which way they rotate polarized light. Thesymbols “R” and “S” represent the configuration of groups around astereogenic carbon atom(s).

An example of an enantiomerically enriched form isolated from a racemicmixture includes a dextrorotatory enantiomer, wherein the mixture issubstantially free of the levorotatory isomer. In this context,substantially free means the levorotatory isomer may, in a range,comprise less than 25% of the mixture, less than 10%, less than 5%, lessthan 2% or less than 1% of the mixture according to the formula:

${\% \mspace{11mu} {levorotatory}} = {\frac{\left( {{mass}\mspace{14mu} {levorotatory}} \right)}{\left( {{mass}\mspace{14mu} {dextrorotatory}} \right) + \left( {{mass}\mspace{14mu} {levorotatory}} \right)} \times 100}$

Similarly, an example of an enantiomerically enriched form isolated froma racemic mixture includes a levorotatory enantiomer, wherein themixture is substantially free of the dextrorotatory isomer. In thiscontext, substantially free means the dextrorotatory isomer may, in arange, comprise less than 25% of the mixture, less than 10%, less than5%, less than 2% or less than 1% of the mixture according to theformula:

${\% \mspace{11mu} {dextrorotatory}} = {\frac{\left( {{mass}\mspace{14mu} {dextrorotatory}} \right)}{\left( {{mass}\mspace{14mu} {dextrorotatory}} \right) + \left( {{mass}\mspace{14mu} {levorotatory}} \right)} \times 100}$

The term “geometric isomer” means isomers that differ in the orientationof substituent atoms in relationship to a carbon-carbon double bond, toa cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms(other than hydrogen) on each side of a carbon-carbon double bond may bein an E or Z configuration. In the “E” configuration, the substituentsare on opposite sides in relationship to the carbon-carbon double bond.In the “Z” configuration, the substituents are oriented on the same sidein relationship to the carbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may bein a cis or trans configuration. In the “cis” configuration, thesubstituents are on the same side in relationship to the plane of thering; in the “trans” configuration, the substituents are on oppositesides in relationship to the plane of the ring. Compounds having amixture of “cis” and “trans” species are designated “cis/trans”.

The isomeric descriptors (“R,” “S,” “E,” and “Z”) indicate atomconfigurations and are intended to be used as defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and, as such, are intended tobe included in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents (e.g., organic esters such as ethanolate and the like)and, as such, are also intended to be encompassed within the scope ofthis invention.

Chemical Definitions

As used herein, the following terms are intended to have the followingmeanings (additional definitions are provided where needed throughoutthe Specification). The definitions herein may specify that a chemicalterm has an indicated formula. The particular formula provided is notintended to limit the scope of the invention, but is provided as anillustration of the term. The scope of the per se definition of the termis intended to include the plurality of variations expected to beincluded by one of ordinary skill in the art.

The term “C₁₋₆alkyl,” whether used alone or as part of a substituentgroup, means a straight or branched chain monovalent hydrocarbon alkylradical or alkyldiyl linking group, respectively, comprising from 1 to 6carbon atoms, wherein the radical is derived by the removal of onehydrogen atom from a single carbon atom and the alkyldiyl linking groupis derived by the removal of one hydrogen atom from each of two carbonatoms in the chain, such as, for example methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 2-butyl, tertiary butyl, 1-pentyl, 2-pentyl,3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl and the like. Examples includeC₁₋₄alkyl groups. C₁₋₆alkyl is substituted on one or more availablecarbon chain atoms with one or more substituents when allowed byavailable valences.

The term “C₁₋₆alkoxy” means an alkyl radical or linking group havingfrom 1-6 carbon atoms in a linear or branched arrangement, wherein theradical or linking group is attached through an oxygen linking atom, asin the formula: —O—C₁₋₆alkyl. The term “C₁₋₆alkoxy” also includes a“C₁₋₄alkoxy” radical or linking group having from 1 up to 4 carbon atomsrespectively, such as methoxy, ethoxy, propoxy, butoxy and the like. Analkoxy radical or linking group may be attached to a core molecule andfurther substituted as a linking group where indicated.

The term “heterocyclyl,” whether used alone or as part of a substituentgroup, refers to a saturated or partially unsaturated monocyclic orpolycyclic ring radical derived by the removal of one hydrogen atom froma single carbon or nitrogen ring atom. Typical heterocyclyl radicalsinclude 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,1,3-dioxolanyl, 2-imidazolinyl (also referred to as4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, tetrazolyl, tetrazolidinyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, azetidinyl,azepanyl, hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl,tetrahydro-furanyl, tetrahydro-thienyl, tetrahydro-pyranyl,tetrahydro-pyridazinyl, 1,3-benzodioxolyl (also referred to asbenzo[1,3]dioxolyl), 2,3-dihydro-1,4-benzodioxinyl (also referred to as2,3-dihydro-benzo[1,4]dioxinyl) and the like.

The term “C₁₋₆alkoxy-carbonyl” means a radical of the formula:—C(O)—O—C₁₋₆alkyl, wherein C₁₋₆alkyl is optionally further substituted.

The term “C₁₋₆alkyl-amino” means a radical of the formula: —NH—C₁₋₆alkylor —N(C₁₋₆alkyl)₂, wherein C₁₋₆alkyl is optionally further substituted.

The term “C₁₋₆alkyl-amino-C₁₋₆alkyl” means a radical of the formula:—C₁₋₆alkyl-NH—C₁₋₆alkyl or —C₁₋₆alkyl-N(C₁₋₆alkyl)₂, wherein C₁₋₆alkylis optionally further substituted.

The term “C₁₋₆alkyl-amino-carbonyl” means a radical of the formula:—C(O)—NH—C₁₋₆alkyl or —C(O)—N(C₁₋₆alkyl)₂, wherein C₁₋₆alkyl isoptionally further substituted.

The term “amino” means a radical of the formula: —NH₂.

The term “amino-C₁₋₆alkyl” means a radical of the formula:—C₁₋₆alkyl-NH₂.

The term “halogen” or “halo” means the group chloro, bromo, fluoro oriodo.

The term “trihalo-C₁₋₆alkoxy” means a radical of the formula:—O—C₁₋₆alkyl-(halo)₃, wherein three halogen atoms may be substituted onC₁₋₆alkyl when allowed by available valences and includestrifluoromethoxy, trifluoroethoxy and the like.

The term “trihalo-C₁₋₆alkyl” means a radical of the formula:—C₁₋₆alkyl-(halo)₃, wherein three halogen atoms may be substituted onC₁₋₆alkyl when allowed by available valences and includestrifluoromethyl, trifluoroethyl and the like.

The term “substituted,” refers to a core molecule on which one or morehydrogen atoms have been replaced with one or more functional radicalmoieties. The number that is allowed by available valences limits theamount of substituents. Substitution is not limited to the coremolecule, but may also occur on a substituent radical, whereby thesubstituent radical becomes a linking group.

Therapeutic Use

A first aspect of the present invention is compounds of Formula (I) or aform thereof useful as inhibitors of ATP-protein kinase interactions.

A second aspect of this invention is a composition or medicamentcomprising one or more compounds of Formula (I) or a form thereof.

A third aspect of this invention is the use of one or more compounds ofFormula (I) or a form thereof as protein kinase inhibitors. The aspectof the protein kinases includes serine/threonine kinases and tyrosinekinases. The aspect of the kinases further includes kinase selected fromCDK1, HER2, VEGFR2, or Aurora-A. Also in this aspect, the compounds ofFormula (I) or a form thereof are useful for preventing, treating orameliorating chronic or acute kinase mediated diseases. The aspect of akinase-mediated disease includes an EGFR protein kinase mediatedcytomegalovirus infection. In a related aspect, the compounds of Formula(I) or a form thereof are useful contraceptive agents.

The use of one or more compounds of Formula (I) or a form thereof asprotein kinase inhibitors thus includes use of one or more compounds ofFormula (I) or a form thereof for inhibiting unregulated protein kinaseactivity by contacting a protein kinase or protein kinase receptor withone or more compounds of Formula (I) or a form thereof. Accordingly,inhibiting such unregulated activity includes inhibiting unregulatedexpression or signaling and, thus, includes use of one or more compoundsof Formula (I) or a form thereof for inhibiting unregulated cellproliferation.

A fourth aspect of this invention is a method for ameliorating, treatingor preventing a chronic or acute kinase mediated disease in a patient inneed thereof comprising administering to the patient an effective amountof one or more compounds of Formula (I) or a form thereof.

In this aspect, the chronic or acute disease is mediated by a kinaseselected from CDK1, HER2, VEGFR2, or Aurora-A. Also in this aspect, themethod includes inhibiting unregulated kinase activity in the patient.The aspect of unregulated kinase activity includes unregulated kinaseexpression or signaling, unregulated expression or signaling of a kinaseselected from CDK1, HER2, VEGFR2, or Aurora-A and unregulated expressionor signaling which results in unregulated cell proliferation. The aspectof unregulated cell proliferation includes cancer, metastatic cancercell invasion or metastatic cancer cell migration. The aspect of cancerincludes tumors mediated by the unregulated activity of kinases selectedfrom CDK1, HER2, VEGFR2, or Aurora-A. The aspect of cancer furtherincludes non-small-cell lung cancers, colon cancers, breast cancers andthe like. An aspect of the method includes an amount of one or morecompounds of Formula (I) or a form thereof which is effective to induceremission of a chronic form of a cancer. The aspect of the effectiveamount includes an amount, which is effective at a low dose to inhibitunregulated kinase activity.

A fifth aspect of this invention is a method for use of one or morecompounds of Formula (I) or a form thereof in the preparation of acomposition or medicament for preventing, treating or amelioratingchronic or acute kinase mediated diseases in a patient in need thereof.This aspect of the method includes administering to the patient aneffective amount of a compound of Formula (I) or a form thereof in theform of a composition or medicament.

The term “chronic or acute kinase mediated disease” as used herein,includes, and is not limited to diseases, disorders, syndromes orconditions associated with unregulated kinase activity and diseases,disorders, syndromes or conditions that accompany such activity.

The term “unregulated kinase activity” refers to 1) increased orunregulated kinase expression or signaling, 2) increased kinaseexpression leading to unregulated cell proliferation, 3) increasedkinase signaling leading to unregulated cell proliferation, or 4)mutations leading to constitutive kinase activation. The existence ofunregulated kinase activity may be determined by procedures well knownin the art.

The term “unregulated cell proliferation” refers to cell proliferationof one or more subset of cells in a multicellular organism resulting inharm (such as discomfort or decreased life expectancy) to themulticellular organism.

Tumor cells that result from unregulated cell proliferation use manymechanisms to enhance their survival and spread; and often have highrates of proliferation because growth control signals that keep normalcells in check are defective. Many tumor cells secrete autocrine growthfactors that increase proliferation rates or they induce other cells tosecrete growth factors that they utilize.

Tumor cells grow and spread by dislodging from a primary tumor site,using proteases to digest the extracellular matrix, spreading inresponse to migration cues, allowing them to migrate to certain tissuespreferentially where overexpressed adhesion molecules allow attachmentand growth at the new site. The totality of these and other biologicalprocesses are responsible for the lethal effects of a tumor. A kinaseinhibitor may affect one or more aspects of tumor survival mechanismsand thus be therapeutically useful. Alternatively, a kinase inhibitormay not affect one particular tumor survival mechanism but may still betherapeutically useful by affecting tumor survival by an unknown or asyet unelucidated mechanism of action.

The foregoing methods contemplate that the compounds of Formula (I) or aform thereof are useful for treating, preventing or ameliorating chronicor acute kinase mediated diseases such as, without limitation,osteoarthritis, rheumatoid arthritis, synovial pannus invasion inarthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus,diabetic angiopathy, diabetic retinopathy, retinal vessel proliferation,inflammatory bowel disease, Crohn's disease, ulcerative colitis, bonediseases, transplant or bone marrow transplant rejection, lupus, chronicpancreatitis, cachexia, septic shock, fibroproliferative anddifferentiative skin diseases or disorders, central nervous systemdiseases, neurodegenerative diseases, disorders or conditions related tonerve damage and axon degeneration subsequent to a brain or spinal cordinjury, acute or chronic cancer, ocular diseases, viral infections,heart disease, lung or pulmonary diseases or kidney or renal diseases.

The foregoing methods contemplate that a compound of formula (I) or aform thereof is useful for treating diseases, disorders or conditionssuch as, without limitation, osteoarthritis, rheumatoid arthritis,synovial pannus invasion in arthritis, multiple sclerosis, myastheniagravis, diabetes mellitus, diabetic angiopathy, diabetic retinopathy,retinal vessel proliferation, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, bone diseases, transplant or bone marrowtransplant rejection, lupus, chronic pancreatitis, cachexia, septicshock, fibroproliferative and differentiative skin diseases ordisorders, central nervous system diseases, neurodegenerative diseases,disorders or conditions related to nerve damage and axon degenerationsubsequent to a brain or spinal cord injury, acute or chronic cancer,ocular diseases, viral infections, heart disease, lung or pulmonarydiseases or kidney or renal diseases.

Certain diseases, disorders or conditions further include, withoutlimitation, acute or chronic cancer selected from bladder cancer, brain,head or neck cancer, breast cancer, colorectal cancer, endometrialcancer, epidermoid cancer, esophageal cancer, gastric cancer, gliomacancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cell cancer, Kaposi's sarcoma, leukemia, lymphoma orpapillocarcinoma; and, cancer-associated pathologies selected fromabnormal cell proliferation, unregulated cell proliferation, tumorgrowth, tumor angiopathy, tumor angiogenesis, tumor vascularization ormetastatic cancer cell invasion and migration.

Certain diseases, disorders or conditions further include, withoutlimitation, fibroproliferative and differentiative skin diseases ordisorders selected from papilloma formation, psoriasis, dermatitis,eczema, seborrhea or chemotherapy-induced alopecia; central nervoussystem diseases selected from Alzheimer's disease, Parkinson's diseaseor depression; ocular diseases selected from macular degeneration,diseases of the cornea or glaucoma; viral infections selected frommycotic infection, autoimmune disease or cytomegalovirus; heart diseaseselected from atherosclerosis, neointima formation ortransplantation-induced vasculopathies such as arterial restenosis; lungor pulmonary diseases selected from allergic-asthma, lung fibrosis,pulmonary fibrosis or chronic obstructive pulmonary disorder; and,kidney or renal diseases selected from acute, subacute or chronic formsof glomerulonephritis or membranoproliferative glomerulonephritis,glomerulosclerosis, congenital multicystic renal dysplasia or kidneyfibrosis.

Certain HER2 kinase mediated cancer includes, without limitation,bladder cancer, brain, head or neck cancer, breast cancer, colorectalcancer, gastric cancer, endometrial cancer, esophageal cancer, lungcancer, ovarian cancer, prostate cancer or renal cell cancer.

The term “myasthenia gravis” means a disease having the characteristicfeature of easy fatigue of certain voluntary muscle groups on repeateduse. Muscles of the face or upper trunk are especially likely to beaffected. In most and perhaps all cases, the disease is due to thedevelopment of autoantibodies against the acetylcholine receptor inneuromuscular junctions. Immunization of animals with this receptorprotein leads to a disease with the features of myasthenia gravis.

In reference to “synovial pannus invasion in arthritis,” the term“pannus” means a disease whereby vascularised granulation tissue rich infibroblasts, lymphocytes and macrophages, derived from synovial tissue,overgrows the bearing surface of the joint in rheumatoid arthritis andis associated with the breakdown of the articular surface.

The term “administering” with respect to the methods of the presentinvention, refers to a means for treating, ameliorating or preventing adisease as described herein with a compound specifically disclosed or acompound or prodrug thereof, which would obviously be included withinthe scope of the invention albeit not specifically disclosed for certainof the instant compounds.

Such methods include administering an effective amount of one or morecompounds of Formula (I) or a form, composition or medicament thereof atdifferent times during the course of a therapy or concurrently in acombination form. Such methods further include administering aneffective amount of one or more compounds of Formula (I) or a form,composition or medicament thereof with one or more agents at differenttimes during the course of a therapy or concurrently in a combinationform.

The term “prodrug” refers to a metabolic precursor of a compound ofFormula (I) or a form thereof. In general, a prodrug is a functionalderivative of a compound, which may be inactive when administered to apatient, but is readily convertible in vivo into an active metabolitecompound.

The term “active metabolite” refers to a metabolic product of a compoundthat is effective for preventing, treating or ameliorating a chronic oracute kinase mediated disease. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The term “patient” as used herein, refers to an animal, preferably amammal, and most preferably a human, who has been the object oftreatment, observation or experiment and is at risk of (or susceptibleto) developing a disease or having a disease related to unregulatedkinase activity.

The term “effective amount” refers to that amount of active compound orpharmaceutical agent that elicits the biological or medicinal response(such as inhibiting unregulated kinase activity) in a patient's tissuesystem, animal or human, that is being sought by a researcher,veterinarian, medical doctor, or other clinician, which includespreventing, treating or ameliorating the symptoms of the chronic oracute kinase mediated disease being treated.

The effective amount of a compound of Formula (I) exemplified in such amethod is from about 0.001 mg/kg/day to about 300 mg/kg/day.

The term “composition” refers to a product containing one or morecompounds of Formula (I) or a form thereof (such as a product comprisingthe specified ingredients in the specified amounts, as well as anyproduct which results, directly or indirectly, from such combinations ofthe specified ingredients in the specified amounts).

The term “medicament” refers to one or more compounds of Formula (I) ora form thereof used in a product for use in preventing, treating orameliorating a chronic or acute kinase mediated disease.

A formulation of a composition or medicament of the present invention is“pharmaceutically acceptable” when the molecular entities and componentsused therein are of sufficient purity and quality such that, whenappropriately administered to an animal or a human, the formulation doesnot produce an adverse, allergic or other untoward reaction. Since bothhuman use (clinical and over-the-counter) and veterinary use are equallyincluded within the scope of the present invention, a pharmaceuticallyacceptable formulation would include a composition or medicament foreither human or veterinary use.

The term “combination therapy” refers to the use of one or morecompounds of Formula (I) or a form, composition or medicament thereof incombination with one or more therapeutic agents for preventing, treatingor ameliorating a chronic or acute kinase mediated disease andadvantageously may facilitate the use of a reduced effective dose of thecompound of Formula (I) and/or the therapeutic agent than would berecommended for the treatment of a particular unregulated cellproliferation disorder. Therefore, it is contemplated that the compoundsof this invention can be used before, during or after treatment with aparticular therapeutic agent.

The term “therapeutic agent” refers to chemotherapeutic agents used totreat a kinase mediated cancer or antiviral agents used to treatcytomegalovirus. Chemotherapeutic agents include and are not limited toanti-angiogenic agents, anti-tumor agents, cytotoxic agents, inhibitorsof cell proliferation, radiation therapy and the like or mixturesthereof.

The term “preventing, treating or ameliorating” refers, withoutlimitation, to facilitating the eradication of, inhibiting theprogression of or promoting stasis of a malignancy.

The term “radiation therapy” refers to a therapy that comprises exposingthe patient in need thereof to radiation. The present invention includesa method for administering one or more compounds of Formula (I) or aform, composition or medicament thereof in combination with radiationtherapy. Procedures for administering such therapy are known to thoseskilled in the art. The appropriate scheme of radiation therapy will besimilar to those already employed in clinical therapies wherein theradiation therapy is used alone or in combination with otherchemotherapeutic agents.

Pharmaceutical Compositions

An embodiment of the present invention includes a composition comprisingan admixture of one or more compounds of Formula (I) and/or one or moreforms thereof and one or more excipients.

The forms for a compound of Formula (I) include a salt, ester, prodrugor active metabolite of a compound of Formula (I). The form for acompound of Formula (I) further includes a radiolabeled compound ofFormula (I), whereby at least one hydrogen atom of the compound ofFormula (I) is replaced with a deuterium or tritium atom. Other labelingtechniques known to those skilled in the arts may also be used.

The present invention further includes the use of a process for makingthe composition or medicament comprising mixing one or more of theinstant compounds and an optional carrier; and, includes thosecompositions or medicaments resulting from such a process. Contemplatedprocesses include both conventional and unconventional pharmaceuticaltechniques.

The composition or medicament may take a wide variety of forms toeffectuate mode of administration, including, but not limited to,intravenous (both bolus and infusion), oral, nasal, transdermal, topicalwith or without occlusion, and injection intraperitoneally,subcutaneously, intramuscularly, intratumorally or parenterally. Thecomposition or medicament may be in a dosage unit such as a tablet,pill, capsule, powder, granule, sterile parenteral solution orsuspension, metered aerosol or liquid spray, drop, ampoule,auto-injector device or suppository; for administration orally,parenterally, intranasally, sublingually or rectally or by inhalation orinsufflation.

Compositions or medicaments suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release and sustained release formulations),granules and powders; and, liquid forms such as solutions, syrups,elixirs, emulsions and suspensions. Forms useful for parenteraladministration include sterile solutions, emulsions and suspensions.Alternatively, the composition or medicament may be presented in a formsuitable for once-weekly or once-monthly administration; for example, aninsoluble salt of the active compound, such as the decanoate salt, maybe adapted to provide a depot preparation for intramuscular injection.

The dosage form (tablet, capsule, powder, injection, suppository,teaspoonful and the like) containing one or more compounds of Formula(I) or a form, composition or medicament thereof as an active ingredientcontains an effective amount of the active ingredient necessary to betherapeutically or prophylactically effective.

The composition or medicament may contain from about 0.001 mg to about5000 mg (preferably, from about 0.001 to about 500 mg) of activeingredient and may be constituted into any form suitable for the mode ofadministration selected for a patient in need. A contemplated effectiveamount may range from about 0.001 mg to about 300 mg/kg of body weightper day. A contemplated effective amount may also range from about 0.003to about 100 mg/kg of body weight per day. Another contemplatedeffective amount may range from about 0.1 to about 100 mg/kg of bodyweight per day. Another contemplated effective amount may also rangefrom about 0.005 to about 15 mg/kg of body weight per day. Thecomposition or medicament may be administered according to a dosageregimen of from about 1 to about 5 times per day.

For oral administration, the composition or medicament is preferably inthe form of a tablet containing, e.g., 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. Optimal dosages will vary depending onfactors associated with the particular patient being treated (e.g., age,weight, diet and time of administration), the severity of the conditionbeing treated, the compound being employed, the mode of administrationand the strength of the preparation. The use of either dailyadministration or post-periodic dosing may be employed.

A radiolabeled form of a compound of Formula (I), whereby at least onehydrogen atom of the compound of Formula (I) is replaced with a labelingatom such as a deuterium or tritium atom, may be used as a marker forthe kinase receptor. Other labeling techniques known to those skilled inthe arts may also be used.

A representative compound of Formula (I) or a form thereof for use inthe therapeutic methods and pharmaceutical compositions, medicines ormedicaments described herein includes a compound selected from the groupconsisting of:

Cpd Name 1 ethyl-(5-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-pyridin-3-ylmethyl)-amine, 26-methoxy-2-[4-(2-pyridin-3-yl-vinyl)-1H-pyrazol-3-yl]-1H-benzoimidazole, 35-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-pyridin-2-ylamine, 42-{4-[2-(6-chloro-pyridin-3-yl)-vinyl]-1H-pyrazol-3-yl}-6-methoxy-1H-benzoimidazole, 56-methoxy-2-{4-[2-(4-methyl-pyridin-3-yl)-vinyl]-1H-pyrazol-3-yl}-1H-benzoimidazole, 64-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-isoquinoline, 86-(4-methyl-piperazin-1-yl)-2-[4-(2-pyridin-3-yl-vinyl)-1H-pyrazol-3-yl]-1H-benzoimidazole, 95-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-nicotinic acid methyl ester, 106-methoxy-2-{4-[2-(5-methoxy-pyridin-3-yl)-vinyl]-1H-pyrazol-3-yl}-1H-benzoimidazole, and 11N-ethyl-5-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-nicotinamide.

Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes and specific examples are offered by way ofillustration; the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The methods forpreparing the various starting materials used in the schemes andexamples are well within the skill of persons versed in the art. Noattempt has been made to optimize the yields obtained in any of theexample reactions. One skilled in the art would know how to increasesuch yields through routine variations in reaction times, temperatures,solvents and/or reagents.

The terms used in describing the invention are commonly used and knownto those skilled in the art. When used herein, the followingabbreviations or formulas have the indicated meanings:

Abbreviation Meaning BHT butylated hydroxytoluene Cpd compound DMFN,N-dimethyl formamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOHethanol Et₂O diethyl ether HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOAc acetic acid MeOH methanolNaH sodium hydride NaOAc sodium acetate min/h/hr/mpminute/hour/day(s)/melting point Pd(dppf)Cl₂•DCMDichloro[1,1′-ferrocenylbis(diphenyl- phosphine)]palladium(II)dichloromethane RT/R.T./rt/r.t. room temperature SEM-Cl2-(trimethyl-silyl)-ethoxymethyl chloride Et₃N triethylamine THFtetrahydrofuran

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

4-iodo-1H-pyrazole-3-carboxylic acid Compound A1 is reacted with4-methoxy-benzene-1,2-diamine dihydrochloride in a reagent solution(such as a mixture of HATU and dipropylethylamine in a solvent such asDMF) to provide a Compound A2.

Compound A2 is reacted with a weak acid (such as acetic acid) to providea Compound A3.

Compound A3 is reacted with a reagent solution (such as a NaH in asolvent such as DMF) then treated with a PG (protecting group) solution(such as SEM-Cl in a solvent such as DMF) to provide a Compound A4.

Compound A3 is reacted with tri-butyl-vinyl tin in the presence of acatalyst solution (such as tetrakis(triphenylphosphine) palladium in asolvent such as DMF) to provide a Compound A5.

Compound A5 is reacted with a substituted pyridine (wherein Q representsa halogen leaving group) in the presence of a complexed catalystsolution (such as Pd(dppf)Cl₂.DCM and a reagent solution (such as amixture of Et₃N and BHT in a solvent such as DMF) to provide a CompoundA6.

Compound A6 is deprotected using standard techniques to provide acompound of Formula (Ib). The compound of Formula (Ib) may be furthersubstituted using standard functional group transformations known tothose skilled in the art to provide additional compounds representativeof the present invention.

SPECIFIC SYNTHETIC EXAMPLES

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The depicted intermediates may alsobe used in subsequent examples to produce additional compounds of thepresent invention. No attempt has been made to optimize the yieldsobtained in any of the reactions. One skilled in the art would know howto increase such yields through routine variations in reaction times,temperatures, solvents and/or reagents.

General: ¹H and ¹³ C NMR spectra were obtained at 400 MHz and 300 MHz ona Brucker AVANCE300 and AVANCE400 spectrometer. Chemical shifts arereported in ppm downfield from TMS as an internal standard. Magnesiumsulfate was employed to dry organic extracts prior to concentration byrotary evaporation. Flash chromatography was done using EM sciencesilica gel 60 (230-400 mesh). Standard solvents from J. T. Baker wereused as received. Anhydrous solvents from Aldrich or J. T. Baker and allother commercially available reagents were used without furtherpurification. Silica gel (E. Merck, 230-400 mesh) was used for all flashchromatography. Thin-layer chromatography was performed on precoatedplates with silica gel 60 F254 from EM Science. Yields were notoptimized. Mass electrospray positive or negative spectra (MS) wasperformed on Hewlett Packard 1100 series or Agilent 1100 seriesspectrometer with a Zorbax stablebond C18 narrow bore column, usinggradient 0.05% acetic acid in methanol and 0.05% acetic acid in water asmobile phase for MS analysis, and using gradient 0.05% TFA inacetonitrile and 0.05% acetic acid in water as mobile phase for LCMSanalysis. HPLC quantitative purity analysis were additionally carried onAgilent 1100 Series LC/MSD equipment on a Agilent 4.6×50 mm Zorbax 3.5uM column (Elips XDB-phenyl) using gradient 0.05% TFA acetonitrile and0.05% TFA in water as solvent system and based on the absorption at 254nM.

Example 1ethyl-(5-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-pyridin-3-ylmethyl)-amine(Compound 1)

A suspension of 4-iodo-1H-pyrazole-3-carboxylic acid Compound 1a(500 mg,2.101 mmol), 4-methoxy-benzene-1,2-diamine dihydrochloride (443 mg,2.101 mmol), HATU (799 mg, 2.101 mmol), and diisopropyl ethylamine (815mg, 6.303 mmol) in 15 ml DMF was stirred at 50° C. for 16 hrs. Aftercooled to rt, the mixture was diluted with 150 ml EtOAc, washed withwater (7 times) and brine, then dried with Na₂SO₄. Evaporation give4-iodo-1H-pyrazole-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amideCompound 1b (615 mg, 81.7%) as a yellowish powder. NMR (DMSO): δ 3.70(s, 3H), 6.20 (m, 1H), 6.46 (s, H), 7.12 (d, J=8.0 Hz, 1H), 8.10 (s,1H). MS m/z 358 (MH⁺).

Compound 1b (100 mg, 0.279 mmol) was suspended in 10 ml of acetic acid.The mixture was stirred at 90° C. for 12 hrs. Acetic acid was evaporatedand residue dissolved into 20 ml EtOAc, washed with saturated NaHCO₃,water and brine. Evaporation gave a brown oil which was treated withCH₂Cl₂ to provide 2-(4-iodo-1H-pyrazol-3-yl)-6-methoxy-1H-benzoimidazoleCompound 1c (62 mg, 94.9%) as a tan powder. NMR (DMSO): δ 3.82 (s, 3H),6.82 (s, 1H), 7.00 (s, 1H), 7.52 (s, 1H), 8.13 (s, 1H). MS m/z 340(MH⁺).

Compound 1c (50 mg, 0.146 mmol) was added to NaH (60% in oil; 17 mg,0.441 mmol) in 5 ml DMF. The mixture was stirred at rt for 10 min. and asolution of SEM-Cl (73 mg, 0.441 mmol) in 2 ml DMF was added. Themixture was stirred at rt for 8 hrs, then diluted with 100 ml EtOAc andwashed with water (6 times) and brine. The crude product was purified bycolumn chromatography to provide2-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazoleCompound 1d (50 mg, 57%) as a mixture of regioisomers.

Isomer 1: NMR (CDCl₃): δ 0.02 (s, 9H), 0.12 (s, 9H), 0.91 (t, J=7.2 Hz,2H), 1.04 (t, J=7.1 Hz, 2H), 3.50 (t, J=7.1 Hz, 2H), 3.71 (t, J=7.2 Hz,2H), 3.98 (s, 3H), 5.60 (s, 2H), 5.95 (s, 2H), 7.05 (m, 1H), 7.15 (s,1H), 7.8˜8.0 (m, 2H).

Isomer 2: NMR (CDCl₃): δ-0.12 (s, 9H), 0.00 (s, 9H), 0.77 (t, J=7.1 Hz,2H), 0.94 (t, J=7.2 Hz, 2H), 3.46 (t, J=7.1 Hz, 2H), 3.60 (t, J=7.2 Hz,2H), 3.89 (s, 3H), 5.48 (s, 2H), 5.72 (s, 2H), 6.98 (m, 1H), 7.38 (s,1H), 7.45 (d, J=5 Hz, 1H), 7.89 (s, 1H). MS m/z 600 (MH⁺).

To a solution of Compound 1d (230 mg, 0.383 mmol) andtetrakis(triphenylphosphine) palladium (44 mg) in 30 ml DMF was added asolution of tri-butyl-vinyl tin (182 mg, 0.574 mmol) in 20 ml oftoluene. The reaction vessel was flushed with N₂ gas and sealed. Themixture was stirred at 70° C. for 10 hrs then diluted with 100 ml EtOAcand washed with water (6 times) and brine. The crude product waspurified by column chromatography to provide6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-2-[1-(2-trimethylsilanyl-ethoxymethyl)-4-vinyl-1H-pyrazol-3-yl]-1H-benzoimidazoleCompound 1e (102 mg, 53.2%) as a pale yellowish oil mixture ofregioisomers.

Isomer 1: NMR (CDCl₃): δ-1.2 (s, 9H), 0.00 (s, 9H), 0.80 (t, J=7.1 Hz,2H), 0.95 (t, J=7.2 Hz, 2H), 3.45 (t, J=7.2 Hz, 2H), 3.62 (t, J=7.1 Hz,2H), 3.92 (s, 3H), 5.20 (d, J=10 Hz, 1H), 5.44 (s, 2H), 5.53 (d, J=13Hz, 1H), 5.93 (s, 2H), 6.92 (m, 1H), 7.04 (s, 1H), 7.20 (dd, J₁=13 Hz,J₂=10 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.85 (s, 1H).

Isomer 2: NMR (CDCl₃): δ-1.50 (s, 9H), 0.00 (s, 9H), 0.78 (t, J=7.1 Hz,2H), 0.96 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.2 Hz, 2H), 3.63 (t, J=7.1 Hz,2H), 3.88 (s, 3H), 5.22 (d, J=10 Hz, 1H), 5.46 (s, 2H), 5.55 (d, J=13Hz, 1H), 5.95 (s, 2H), 6.95 (m, 1H), 7.22 (dd, J₁=13 Hz, J₂=10 Hz, 1H),7.30 (s, 1H), 7.45 (d, J=7 Hz, 1H), 7.86 (s, 1H). MS m/z 501 (MH⁺)

A suspension of Compound 1e (102 mg, 0.204 mmol),5-bromo-pyridine-3-carbaldehyde (38 mg, 0.204 mmol), Pd(dppf)Cl₂.DCM (33mg, 0.04 mmol), Et₃N (62 mg, 0.61 mmol) and 3 mg BHT in 20 ml of DMF washeated at 90° C. in a sealed tube for 8 hrs. The reaction mixture wasdiluted with 100 ml EtOAc, then washed with water (6 times) and brine.The crude product was purified by column chromatography to provide5-{2-[3-[6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-vinyl}-pyridine-3-carbaldehydeCompound 1f (35 mg, 28%) as colorless oil mixture of regioisomers.

Mixture: NMR (CDCl₃): δ-0.2˜0.00 (M, 18H), 0.82 (m, 2H), 0.95 (t, J=7.2Hz, 2H), 3.50 (m, 2H), 3.68 (t, J=7.2 Hz, 2H), 3.90 (s, 3H), 5.48 (s,2H), 6.01 (s, 2H), 6.8˜9.0 (m, 9H), 10.10 (s, 1H). MS m/z 605 (MH⁺)

To a solution of Compound 1f (35 mg, 0.058 mmol) in 10 ml of MeOH wasadded 1 ml of 2M ethylamine solution in THF. The mixture was stirred atrt for 2 hrs and 300 mg NaBH₄ powder was added portionwise. The mixturewas stirred at rt for 8 hrs, the MeOH was evaporated and the residuepartitioned between water and EtOAc. The organic layer was isolated,dried and the solvent evaporated to give a crude product, which waspurified by column chromatography to provideethyl-(5-{2-[3-[6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-vinyl}-pyridin-3-ylmethyl)-amineCompound 1g (20 mg, 54.5%) as colorless oil mixture of regioisomers.

Mixture: NMR (CDCl₃): δ 0.3˜0.1 (m, 18H), 0.82 (m, 2H), 0.95 (t, J=7.0Hz, 2H), 1.15 (m, 3H), 2.70 (m, 2H), 3.48 (m, 2H), 3.65 (t, J=7.0 Hz,2H), 3.83 (s, 2H), 3.90 (s, 3H), 5.48 (s, 2H), 5.97 (s, 2H), 6.8˜8.7 (m,9H). MS m/z 635 (MH⁺)

Compound 1g (20 mg, 0.031 mmol) was dissolved in 5 ml EtOH and 5 ml of4N HCl was added. The solution was refluxed for 12 hrs and evaporated todryness. The residue was recrystallized by EtOH/Et₂O to provide thetrihydrochloride salt of Compound 1 (11 mg, 72% yield) as a pale yellowpowder. NMR (CD₃OD): δ 1.46 (t, J=6.8 Hz, 3H), 3.25 (q, J=6.8 Hz, 2H),3.45 (s, 3H), 4.54 (s, 2H), 7.22 (dd, J₁=8 Hz, J₂=2 Hz, 1H), 7.37 (d,J=14 Hz, 1H), 7.42 (d, J=2 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 8.03 (d, J=14Hz, 1H), 8.53 (s, 1H), 8.92 (s, 1H), 9.15 (s, 1H), 9.44 (s, 1H). MS: 375(M+1) m.p.: 267 (dec.).

Using the procedure of Example 1 and the appropriate starting materials,reagents and conditions known to those skilled in the art, othercompounds representative of the present invention were prepared:

Cpd Name MS 2 6-methoxy-2-[4-(2-pyridin-3-yl-vinyl)-1H-pyrazol-3-yl]-318 1H-benzoimidazole 35-{2-[3-(6-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4- 333yl]-vinyl}-pyridin-2-ylamine 42-{4-[2-(6-chloro-pyridin-3-yl)-vinyl]-1H-pyrazol-3- 352yl}-6-methoxy-1H-benzoimidazole 56-methoxy-2-{4-[2-(4-methyl-pyridin-3-yl)-vinyl]-1H- 332pyrazol-3-yl}-1H-benzoimidazole 64-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4- 368yl]-vinyl}-isoquinoline 75-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4- 343yl]-vinyl}-nicotinonitrile 86-(4-methyl-piperazin-1-yl)-2-[4-(2-pyridin-3-yl-vinyl)- 3861H-pyrazol-3-yl]-1H-benzoimidazole 95-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4- 376yl]-vinyl}-nicotinic acid methyl ester 106-methoxy-2-{4-[2-(5-methoxy-pyridin-3-yl)-vinyl]-1H- 348pyrazol-3-yl}-1H-benzoimidazole 11N-ethyl-5-{2-[3-(6-methoxy-1H-benzoimidazol-2-yl)-1H- 389pyrazol-4-yl]-vinyl}-nicotinamide

Biological Examples

The ability of the compounds to treat or ameliorate protein kinasemediated disorders was determined using the following procedures.

Example 1 CDK-1, VEGFR2, HER2, and Aurora-A Screening Assays

A kinase reaction mixture was prepared containing 50 mM Tris-HCl pH=8,10 mM MgCl₂, 0.1 mM Na₃PO₄, 1 mM DTT, 10 μM ATP, 0.025 μM biotinylatedhistone-H1 peptide substrate and 0.2 μCuries per well ^(33P)-γ-ATP(2000-3000 Ci/mmol). 70 μL of the kinase reaction mixture was dispensedinto the well of a streptavidin coated FlashPlate™ (Cat. # SMP103, NEN,Boston, Mass.).

Test compound stock in 100% DMSO (1 μL) was added to the wells resultingin a final concentration of 1% DMSO in the reaction with a 100 μL finalreaction volume. Each enzyme was diluted in 50 mM Tris-HCl pH=8.0, 0.1%BSA and 30 μL was added to each well to initiate the reaction. Thereaction was incubated for one hour at 30° C. At the end of the 1 hrincubation, the reaction was terminated by aspirating the mixture fromthe plate and washing the wells twice with PBS containing 100 mM EDTA.The biotinylated peptide substrate became immobilized on the Flashplate™and the incorporation of ³³P-γ-ATP was measured by reading the plate ona scintillation counter. Inhibition of the enzymatic activity wasmeasured by observing a reduced amount of ³³P-γ-ATP incorporated intothe immobilized peptide.

The CDK1 enzyme was isolated from insect cells expressing both the humanCDK1 catalytic subunit (Accession number NM_(—)001786) and its positiveregulatory subunit cyclin B (New England Biolabs, Beverly, Mass.; Cat. #6020). The assay used 30 ng of the N-terminal biotinylated peptidebiotin-KTPKKAKKPKTPKKAKKL-amide (Cyclin dependent kinase 1) per well.

The VEGF-R2 enzyme is a fusion protein containing a polyhistidine tag atthe N terminus followed by amino acids 786 to 1343 of the rat VEGF-R2kinase domain (Accession number U93306). The assay used 150 ng of theN-terminal biotinylated peptide biotin-AEPDYGALYEGRNPGFYVEANP-amide(VEGF-R2) per well.

The HER2 construct consisted of a fusion of GST(Glutathione-S-Transferase), HIS6 Thrombin and the nucleotides encodingamino acids 679 to 1255 of HER-2 (Accession number M11730) (Proqinase,Freiburg, Germany). The assay used 200 ng of the N-terminal biotinylatedpeptide biotin-poly(GT) 4:1 (HER2) per well.

Aurora-A is a fusion protein containing a polyhistidine tag at the Nterminus followed by the full length protein encoding the murineAurora-A (Accession number GB BC014711) expressed and purified from sf9insect cells. The assay used 400 ng of the N-terminal biotinylatedpeptide biotin-GRTGRRNSI-amide (Aurora-A) per well. A maximum andminimum signal for the assay was determined on each plate. The percentinhibition of a test compound was calculated according to the formula:

${\left\lbrack \frac{\left( {{\max \mspace{14mu} {signal}} - {{test}\mspace{14mu} {compound}}} \right)}{\left( {{\max \mspace{14mu} {signal}} - {\min \mspace{14mu} {signal}}} \right)} \right\rbrack (100)} = {\% \mspace{11mu} {inhibition}}$

For a series of test concentrations, the IC₅₀ was derived by graphingpercent inhibition against the log of the concentrations tested for agiven compound with results shown in Table 1.

TABLE 1 IC₅₀ (average) (μM) Cpd CDK1 HER2 VEGFR2 Aurora-A 1 0.0045953.032 0.8211 0.58847 2 0.03285 >10 0.9665 0.5133 3 0.02302 6.836 0.6360.6249 5 0.15723 >10 0.7586 0.5485 6 0.14797 >100 0.6126 0.53257 >1 >100 1.733 4.192 8 0.0291 9.323 0.2859 >10 9 0.8864 >100 1.277 >10010 0.04658 11.98 0.6528 0.3988 11 0.1109 36.65 1.348 >100

Example 2 Cell Proliferation Inhibition Assay

The ability of a test compound to inhibit unregulated cell proliferationmay be determined by measuring incorporation of ¹⁴C-labelled thymidineinto newly synthesized DNA within cell lines derived from carcinomasoriginating from several tissues. Accordingly, the anti-proliferativeeffect of a compound on cells with a variety of phenotypes may bedetermined.

Carcinoma cell lines include those such as HeLa cervical adenocarcinoma(American Type Culture Collection (ATCC), Virginia, Cat. #CCL-2), A375malignant melanoma (ATCC CRL-1619), and HCT-116 colon carcinoma(CCL-247).

The carcinoma cells are trypsinized and counted. The cells (3000-8000count) are added to each well of a 96-well CytoStar tissue culturetreated scintillating microplate (Amersham #RPNQ0160) in complete medium(100 μL) and the plate is then incubated in complete medium for 24 hrsat 37° C. in an inert atmosphere containing 5% CO₂. Test compound (1 μL)in 100% DMSO is added to the plate test-wells with DMSO only added tocontrol-wells. The plate is incubated in complete medium for a second 24hr period at 37° C. in an atmosphere containing 5% CO₂.

An aliquot of a solution of Methyl ¹⁴C-thymidine (56 mC/mmol) (NEN#NEC568 or Amersham #CFA532) and complete medium (20 uL to provide 0.2μCi/well) is then added to each well and the plate is incubated for athird 24 hr period at 37° C. in an atmosphere containing 5% CO₂. Theplate contents are then discarded, the plate is washed twice with PBS(200 μL) and then PBS (200 μL) is added to each well. The plate issealed and the degree of methyl ¹⁴C-thymidine incorporation isquantified on a Packard Top Count.

A maximum and minimum signal for the assay was determined on each plate.The percent inhibition of a test compound was calculated according tothe formula:

${\left\lbrack \frac{\left( {{\max \mspace{14mu} {signal}} - {{test}\mspace{14mu} {compound}}} \right)}{\left( {{\max \mspace{14mu} {signal}} - {\min \mspace{14mu} {signal}}} \right)} \right\rbrack (100)} = {\% \mspace{11mu} {inhibition}}$

For a series of test concentrations, the IC₅₀ was derived by graphingpercent inhibition against the log of the concentrations tested for agiven compound with results shown in Table 3.

TABLE 2 IC₅₀ (average) (μM) Cpd A375 HCT-116 HeLa 1 0.55303 0.187290.61547 2 2.495 2.156 1.798 3 1.031 1.036 0.9917 5 4.297 3.19 2.76 62.963 2.676 2.825 7 NT NT NT 8 0.864 0.1945 0.4643 9 3.097 3.128 4.36710 0.9128 0.7485 0.8859 11 3.623 2.458 3.701

Example 3 In Vivo Models-Inhibition of Tumor Growth

The ability of a test compound to inhibit unregulated growth of humantumor cells in vivo may be evaluated by implanting human tumor cellsinto the hindflank of athymic mice, administering a test compound andthen quantifying any change in tumor size.

Human epidermoid A431 carcinoma cells (10⁶ count) are implantedsubcutaneously into the hindflank of female athymic mice (Charles River)and allowed to grow for 6-10 days. After a measurable tumor isestablished (as determined by baseline caliper measurement), the animalis administered an oral dose of the test compound (in 10% solutol) dailyfor a period of 30 days. Tumor size is measured every five days and thedegree of inhibition is determined by comparing drug-treated animals tovehicle-treated animals.

Variations of this method are intended to include intraperitonealinjection or intravenous infusion as the route of administration andadministration of the test compound either alone or in a combinationtherapy.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and modifications as come within thescope of the following claims and their equivalents.

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

1. A compound of Formula (I):

R₁ is hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, amino orC₁₋₆alkyl-amino; R₂ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,C₁₋₆alkyl-amino, amino-C₁₋₆alkyl, C₁₋₆alkyl-amino-C₁₋₆alkyl,C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano; R₃ is hydrogenor C₁₋₆alkyl; alternatively, R₂ and R₃ are taken together to form—CH═CH—CH═CH—; and, R₄ is hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy orheterocyclyl, wherein said heterocyclyl is optionally substituted withC₁₋₆alkyl.
 2. The compound of claim 1, wherein R₁ is hydrogen, chloro oramino; R₂ is hydrogen, methoxy, ethyl-amino-methyl, methoxy-carbonyl,ethyl-amino-carbonyl or cyano; R₃ is hydrogen or methyl; alternatively,R₂ and R₃ are taken together to form —CH═CH—CH═CH— or a form thereof 3.The compound of claim 1 wherein R₄ is hydrogen, methoxy or piperazine,wherein piperazine is substituted with methyl, or a form thereof.
 4. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of

and forms thereof.
 5. (canceled)
 6. The compound of claim 1 wherein thecompound is in an isolated form.
 7. (canceled)
 8. (canceled)
 9. A methodfor ameliorating, treating or preventing a chronic or acute kinasemediated disease in a patient in need thereof comprising administeringto the patient an effective amount of a compound of Formula (I):

R₁ is hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, amino orC₁₋₆alkyl-amino; R₂ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,C₁₋₆alkyl-amino, amino-C₁₋₆alkyl, C₁₋₆alkyl-amino-C₁₋₆alkyl,C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano; R₃ is hydrogenor C₁₋₆alkyl; alternatively, R₂ and R₃ are taken together to form—CH═CH—CH═CH—; and, R₄ is hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy orheterocyclyl, wherein said heterocyclyl is optionally substituted withC₁₋₆alkyl.
 10. The method of claim 9 wherein the chronic or acutedisease is mediated by unregulated kinase activity, unregulated kinaseexpression or signaling or unregulated cell proliferation as a result ofunregulated kinase activity, expression or signaling.
 11. The method ofclaim 10 wherein the kinase is selected from CDK1, HER2, VEGFR2, orAurora-A.
 12. The method of claim 9 wherein the chronic or acute diseaseis selected from osteoarthritis, rheumatoid arthritis, synovial pannusinvasion in arthritis, multiple sclerosis, myasthenia gravis, diabetesmellitus, diabetic angiopathies or retinopathy, inflammatory boweldisease, Crohn's disease, ulcerative colitis, transplant or bone marrowtransplant rejection, lupus, chronic pancreatitis, cachexia, septicshock, skin diseases or disorders, central nervous system diseases,cancers, ocular diseases, viral infections, heart disease, lung orpulmonary diseases or kidney or renal diseases.
 13. The method of claim12 wherein skin diseases or disorders are selected from papillomaformation, psoriasis, dermatitis, eczema or seborrhea; central nervoussystem diseases are selected from Alzheimer's disease, Parkinson'sdisease or depression; cancers are selected from glioma cancers,epidermoid cancers, head and neck cancers, lung cancers, breast cancers,colorectal cancers, prostate cancers, gastric cancers, esophagealcancers or papillocarcinomas and associated pathologies such asunregulated cell proliferation, tumor growth or vascularization ormetastatic cancer cell invasion and migration or leukemias or lymphomas;ocular diseases are selected from macular degeneration, diseases of thecornea or glaucoma; viral infection is selected from cytomegalovirus;heart disease is selected from atherosclerosis, neointima formation ortransplantation-induced vasculopathies or restenosis, lung or pulmonarydiseases are selected from allergic-asthma, lung fibrosis orcomplications resulting from chronic obstructive pulmonary disorder;kidney or renal diseases are selected from acute, subacute or chronicforms of glomerulonephritis or membranoproliferative glomerulonephritis,glomerulosclerosis, congenital multicystic renal dysplasia or kidneyfibrosis.
 14. The method of claim 9 wherein the effective amount of thecompound is from about 0.001 mg/kg/day to about 300 mg/kg/day.
 15. Themethod of claim 14 wherein the amount of the compound is effective toinduce remission of a chronic form of a cancer.
 16. The method of claim14 wherein the amount of the compound is effective at a low dose toinhibit unregulated kinase activity.
 17. (canceled)
 18. A pharmaceuticalcomposition comprising a compound of Formula (I):

R₁ is hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, amino orC₁₋₆alkyl-amino; R₂ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,C₁₋₆alkyl-amino, amino-C₁₋₆alkyl, C₁₋₆alkyl-amino-C₁₋₆alkyl,C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-amino-carbonyl or cyano; R₃ is hydrogenor C₁₋₆alkyl; alternatively, R₂ and R₃ are taken together to form—CH═CH—CH═CH—; and R₄ is hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy orheterocyclyl, wherein said heterocyclyl is optionally substituted withC₁₋₆alkyl; and a pharmaceutically acceptable carrier.